Chimeric antibodies

Abstract

The invention relates to murine / human chimeric monoclonal antibodies with high specificity to and affinity for human carcinoembryonic antigen (CEA), derivatives thereof, processes for the preparation of these antibodies and their derivatives, DNAs coding for heavy and light chains of these antibodies, processes for the preparation of said DNAs, mammalian cell lines that produce and secrete the antibodies and processes for the preparation of said cell lines. The chimeric antibodies and their derivatives are used for clinical purposes in vitro and in vivo, especially for the diagnosis of cancer, for localization and in vivo imaging of tumors, for therapy, e.g. site-directed delivery of cytotoxins, and similar purposes. The invention also concerns test kits and pharmaceutical compositions containing said chimeric monoclonal antibodies and / or derivatives thereof.

Description

This invention relates to mouse / human chimeric monoclonal antibodies with high specificity to and affinity for human carcinoembryonic antigen (CEA), derivatives thereof, processes for the preparation of these antibodies and their derivatives, DNAs coding for heavy and light chains of these antibodies, processes for the preparation of said DNAs, mammalian cell lines that produce and secrete the antibodies, processes for the preparation of said cell lines, the use of the chimeric monoclonal antibodies and their derivatives for the diagnosis and therapy of cancer, test kits containing the chimeric monoclonal antibodies, and pharmaceutical preparations containing said antibodies.Immunoglobulins (antibodies) play an important role in the immune system of mammals. They are produced by plasma cells and consist of two identical light (L) polypeptide chains and two identical heavy (H) polypeptide chains joined by disulfide bridges, or polymers of this basic four chain unit. The light chains ...

AI Technical Summary

Benefits of technology

high percentage of binding to CEA-carrying carcinoma cells, both in vitro a

Problems solved by technology

However, a major limitation in the use of murine-derived monoclonal antibodies as in vivo diagnostic and therapeutic agents is their immunogenicity as foreign proteins, their rather long persistence in the circulation, and the formation of damaging immune complexes.

On the other hand, the treatment with human monoclonal antibodies is limited also since human hybridoma cell lines are rarely available, usually unstable and do not produce monoclonal antibodies of appropriate specificity in sufficient quantities and at reasonable costs.

Depending on the source of the genes to be combined and on the nature of the genes coding for the antigen-specific variable region, however, particular problems arise so that new and inventive steps are required to develop workable solutions.

The secreted IgM, however, was not as effective as the original mouse IgM and showed different binding qualities.

One of the major drawbacks of the use of anti-CEA antibodies for the above purposes has been the cross-reactivity of these reagents with some apparently normal adult tissues.

It is well established, however, that prokaryotic cells do not provide the necessary steps for biosynthesis of functional tetrameric antibodies, such as correct nascent polypeptide chain folding, glycosylation and assembly.

The conceptual approach to the production of chimeric antibodies in the above cited patent application therefore lacks the basis for the expression of the recombinant gene constructs and thus, the secretion of active monoclonal antibodies.

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